The balance between proinflammatory mechanisms and the dampening of excessive immune activation is important for treatment of infectious disease and also for treatment of autoimmune disease. The former benefits from an activated immune system while the latter requires reduce immune system activity. Thus, the immune system has the reciprocal tasks to protect the host against invading pathogens, but simultaneously to prevent damage resulting from unwanted reactions to self antigens.
The latter part is known as immune tolerance and performed by a complex set of interactive and complementary pathways, which regulate immune responses. T cells have the ability to react to a variety of antigens, both self and nonself. Therefore, there are many mechanisms that exist naturally to eliminate potentially self-reactive responses—this is known as natural tolerance. The main mechanism for eliminating potential auto-reactive T cells occurs in the thymus and is known as central tolerance. Some potentially autoreactive T cells escape central tolerance and, therefore, peripheral tolerance mechanisms also exist. Despite these mechanisms, some self-reactive T cells may ‘escape’ and be present in the repertoire; it is believed that their activation may lead to autoimmune disease.
Studies on therapeutic tolerance have attempted to induce and amplify potent physiological mechanisms of tolerance in order to eliminate or neutralize self-reactive T cells and prevent or treat autoimmune diseases. One way to induce tolerance is by manipulation of the interaction between costimulatory ligands and receptors on antigen presenting cells (APCs) and lymphocytes.
CTLA-4 is the most extensively studied costimulatory molecule which down-regulates immune responses. The attributes of immunosuppressive qualities and capacity to induce tolerance have made its recognition as a potential immuno-therapeutic agent for autoimmune mediated inflammatory disorders. Abatacept (commercial name: Orencia) is a fusion protein composed of the ECD (extracellular domain) of CTLA-4 fused to the Fc fragment of hIgG1. Abatacept is believed to induce costimulation blockade, which has been approved for treating patients with rheumatoid arthritis, by effectively interfering with the inflammatory cascade.
Induction of disease control with the current therapies, followed by progressive withdrawal in parallel with re-establishing immune tolerance, may be an attractive approach in the future of autoimmune therapies. Furthermore, due to their immune specificity, in the absence of global immunosuppression, such therapies should be safer.
T helper type 1 (Th1) cells are induced by IL-12 and produce IFN-γ, while T helper type 2 (Th2) cells secrete IL-4, IL-5 and IL-13. Th1 cells can mediate proinflammatory or cell-mediated immune responses, whereas Th2 cells mainly promote certain types of humoral immunity. Some immune related diseases, such as autoimmune reactions, inflammation, and infection, are characterized by a dysregulation of the pro-versus anti-inflammatory tendencies of the immune system, as well as an imbalance in the Th1 versus Th2 cytokine balance. During inflammation, induction of a shift in the balance from Th1 to Th2 protects the organism from systemic ‘overshooting’ with Th1/pro-inflammatory cytokines, by reducing the inflammatory tendencies of the immune system Immunomodulatory therapies that are associated with a Th1 to Th2 immune shift have protective effects in Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. For example, Laquinimod, which has demonstrated efficacy in animal models of several autoimmune diseases including MS, shows immunomodulatory effects through Th1/Th2 shift, and does not lead to immunosuppression. Glatiramer acetate (Copaxone) also induces Th1/Th2 shift with decreased secretion of proinflammatory cytokines, and increased secretion of antiinflammatory cytokines. Furthermore, GA-specific Th2 cells are able to migrate across the blood-brain barrier and cause in situ bystander suppression of autoaggressive Th1 T cells.
The balance between proinflammatory mechanisms and the dampening of excessive immune activation is also critical for successful clearance of a pathogen without harm to the host. Excessive immune activation may lead to autoimmune attacks, while too little immune activation will not result in clearance of the pathogen from the host. Chronic pathogens exploit co-inhibitory pathways to attenuate Ag-specific T cell immunity. Emerging data from a wide range of studies on acute and chronic infections support an important role for negative costimulatory receptors in controlling infection. Most notably, exhausted T cells, functionally impaired T cells which are present during chronic infection and are characterized by reduced proliferative and cytotoxic abilities, express high levels of multiple co-inhibitory receptors such as CTLA-4, PD-1, and LAGS (Crawford et al., Curr Opin Immunol. 2009; 21:179-186; Kaufmann et al., J Immunol 2009; 182:5891-5897, Sharpe et al., Nat Immunol 2007; 8:239-245). Furthermore, the exhausted phenotype can be reversed by blocking co-inhibitory pathways (Rivas et al., J Immunol. 2009; 183:4284-91; Golden-Mason et al., J Virol. 2009; 83:9122-30), thus allowing restoration of anti viral immune function, supporting therapeutic application of co-inhibitory blockade in viral infection.
One potentially promising strategy to control chronic infections such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus is therapeutic vaccination, which aims to reduce persisting virus by stimulating a patient's own antiviral immune responses. However, this approach has fallen short of expectations, because antiviral T cells generated during chronic infections often become functionally exhausted, as explained above, and thus do not respond properly to therapeutic vaccination. Therefore, it is necessary to restore T cell effector functions and effectively boost endogenous T-cell responses in order to develop therapeutic vaccines against chronic viral infections. Blocking the negative signaling pathways, PD-1 and CTLA-4, could restore the host immune system, enabling it to respond to further stimulation. Blockade of the PD-1/PD-L1 pathway, for example, is able to restore functional capabilities to exhausted CTLs (Hofmeyer et al, J. Biomed. & Biotech. Vol. 2011, Art. ID 451694). Combining therapeutic vaccination along with the blockade of inhibitory signals could synergistically enhance functional CD8(+) T-cell responses and improve viral control in chronically infected individuals, providing a promising strategy for the treatment of chronic viral infections. (Ha et al, Immunol Rev. 2008 June; 223:317-33). Antibodies to PD-1 and CTLA-4 are currently in clinical trials in chronic hepatitis C, as promising candidates for combination with both prophylactic and therapeutic vaccines (Diepolder and Obst, Expert Rev Vaccines. 2010 March; 9(3):243-7).
The therapeutic potential of co-inhibition blockade for treating viral infection was extensively studied by blocking the PD-1/PD-L1. Blocking this pathway was shown to be efficacious in several animal models of infection including acute and chronic Simian immunodeficiency virus (SIV) infection in rhesus macaques (Valu et al., Nature 2009; 458:206-210) and in mouse model of chronic viral infection with lymphocytic choriomeningitis virus (LCMV) (Barber et al., Nature. 2006; 439:682-7).
Modulation of costimulatory pathway has also been proven effective in optimizing antiviral immunity by limiting the memory T cell response to its protective capacities (Teijaro et al., J Immunol. 2009: 182; 5430-5438). This has been demonstrated in models of influenza infection in which inhibiting CD28 costimulation with CTLA4-Ig suppressed primary responses in naive mice infected with influenza, but was remarkably curative for memory CD4 T cell-mediated secondary responses to influenza leading to improved clinical outcome and increased survival to influenza challenge. The curative effect of CTLA4-Ig on secondary responses was accompanied by inhibition of proliferation and egress of lymphoid naive and memory T cells, while leaving lung resident memory CD4 T cell responses intact thus maintaining enhanced and rapid lung viral clearance mediated by memory CD4 T cells, yet reducing lung immunopathology.
These data demonstrate an active and reversible role for molecules of the B7:CD28 family, PD-1, CTLA-4, and their ligands, in virus-specific T cell exhaustion associated with chronic viral infection and point to promising potential for immunotherapeutic interventions based on manipulation of these inhibitory networks.
Regulating costimulation using agonists and antagonists to various costimulatory proteins has been extensively studied as a strategy for treating autoimmune diseases, graft rejection, allergy and cancer. This field has been clinically pioneered by CTLA4-Ig (Abatacept, Orencia®) that is approved for treatment of RA, and by the anti-CTLA4 antibody (Ipilimumab, Yervoy®), recently approved for the treatment of melanoma. Other costimulation regulators are currently in advanced stages of clinical development including anti PD-1 antibody (MDX-1106) which is in development for treatment of advanced/metastatic clear-cell renal cell carcinoma (RCC) and anti-CD40L Antibody (BG9588, Antova®) for treatment of renal allograft transplantation. In addition, such agents are in clinical development for viral infections, for example the anti PD-1 Ab, MDX-1106, is being tested for treatment of hepatitis C. Another example is CP-675,206 (tremelimumab) and anti-CTLA4 Ab which is in a clinical trial in hepatitis C virus-infected patients with hepatocellular carcinoma.
B cells play a critical role in recognition of foreign antigens and subsequent production of antibodies in the specific humoral adaptive immune responses that provide protection against various types of infectious agents. B cells play a critical role in recognition of foreign antigens and they produce the antibodies necessary to provide protection against various type of infectious agents. T cell help to B cells is a pivotal process of adaptive immune responses. Follicular helper T (Tfh) cells are a subset of CD4+ T cells specialized in B cell help (reviewed by Crotty, Annu. Rev. Immunol. 29: 621-663, 2011). Tfh cells express the B cell homing chemokine receptor, CXCR5, which drives Tfh cell migration into B cell follicles within lymph nodes in a CXCL13-dependent manner. The requirement of Tfh cells for B cell help and T cell-dependent antibody responses, indicates that this cell type is of great importance for protective immunity against various types of infectious agents, as well as for rational vaccine design.
Tfh cells selectively express a wealth of surface proteins, which are involved in their selective localization (such as CXCR5) and in direct physical interactions with B cells to provide B cell help. Among the latter group are several members of the costimulatory proteins family which are highly expressed in Tfh cells, including the inducible co-stimulatory receptor ICOS, and the negative costimulators (inhibitory receptors) PD-1 and BTLA (Crotty, Annu. Rev. Immunol. 29: 621-663, 2011).